Active derivatives of methylamino in therapeutic compositions and methods of use

ABSTRACT

Methylamine derivatives of the formula: ##STR1## and pharmaceutically acceptable acid addition salts thereof, wherein R 1  and R 3  each represent a hydrogen atom or a straight- or branched-chain alkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms, R 2  represents a straight- or branched-chain alkyl, alkenyl or alkynyl radical containing from 2 to 7 carbon atoms with the proviso that when R 2  represents an alkenyl radical of the formula CH.tbd.CH--R 4  or an alkynyl radical of the formula C=C--R 4 , in which R 4  represents a hydrogen atom or a straight- or branched-chain alkyl radical of 1 to 5 carbon atoms, R 1  and R 3  each represent an atom of hydrogen or an alkyl radical, R 1 , R 2  and R 3  being such that no compound of formula I possesses more than 13 carbon atoms. 
     They are useful for treating Parkinson&#39;s disease and for correcting extra-pyramidal disturbances provoked by neuroleptics.

This is a division of application Ser. No. 577,732, filed May 15, 1975.

The present invention relates to pharmacologically active derivatives ofmethylamine and their pharmaceutically acceptable acid addition salts aswell as to pharmaceutical and veterinary compositions containing thesaid derivatives and salts.

The invention also concerns processes for preparing the derivatives ofthe invention and for the preparation of compositions containing them.

The pharmacologically active compounds with which the invention isconcerned correspond to the following general formula: ##STR2## whereinR₁ and R₃ each represent a hydrogen atom or a straight-or branched-chainalkyl, alkenyl or alkynyl radical containing from 1 to 6 carbon atoms,R₂ represents a straight-or branched-chain alkyl, alkenyl or alkynylradical containing from 2 to 7 carbon atoms with the proviso that whenR₂ represents an alkenyl radical of the formula CH=CH--R₄ or an alkynylradical of the formula C.tbd.C--R₄, in which R₄ represents a hydrogenatom or a straight-or branched-chain alkyl radical of 1 to 5 carbonatoms, R₁ and R₃ each represent an atom of hydrogen or an alkyl radical,R₁, R₂ and R₃ being such that no compound of formula I possesses morethan 13 carbon atoms.

The invention also relates to the pharmaceutically acceptable acidaddition salts of the compounds of formula I such as the acid additionsalts obtained with an inorganic acid, for example, hydrochloric acid,or with an organic acid in which the free carboxyl is attached to asaturated or unsaturated aliphatic radical, or an aromatic or aralkylradical which may optionally contain a second carboxyl group such as,for example, fumaric acid.

Another object of the present invention is a pharmaceutical orveterinary composition containing as essential active ingredient atleast one of the methylamine derivatives defined in formula I or apharmaceutically acceptable acid addition salt thereof in associationwith an appropriate pharmaceutical carrier or excipient therefor.

A further object of the invention is to provide a process for preparingpharmaceutical or veterinary compositions whereby at least onemethylamine derivative of formula I or a pharmaceutically acceptableacid addition salt thereof is placed in association with an appropriatepharmaceutical carrier or excipient.

As will be described in greater detail further on, it has been foundthat the methylamine derivatives of formula I and their pharmaceuticallyacceptable acid addition salts possess pharmacological properties likelyto render them particularly useful in the treatment of Parkinson'sdisease and for correcting extra-pyramidal disturbances provoked byneuroleptics.

In consequence, another object of the invention is to provide a methodof trating Parkinson's disease and of correcting extra-pyramidaldisturbances provoked by neuroleptics, which method comprises theadministration to the patient so affected of at least one compound offormula I or a pharmaceutically acceptable acid addition salt thereof.

Daily dosage will preferably be between 10 and 60 mg of active principlefor a human being weighing 60 kg.

Amongst the compounds of formula I, a certain number may be consideredas novel.

The invention relates, in consequence, to the new derivatives ofmethylamine listed below, all of which are included in formula I:

1,1-Diethyl-n-butylamine

1,1-Di-n-propyl-n-propylamine

1-Ethyl-1-isobutyl-n-butylamine

1,1,3-Trimethyl-n-heptylamine

1,1-Dimethyl-3-ethyl-n-hexylamine

1,3-Dimethyl-1-ethyl-n-hexylamine

1,3-Dimethyl-1-n-propyl-n-pentylamine

1-Methyl-1-isobutyl-n-pentylamine

1-Methyl-1-n-propyl-n-hexylamine

1-n-Propyl-1-isobutyl-n-butylamine

1,1-Diisobutyl-n-butylamine

1-Ethyl-1-n-propyl-n-pentylamine

1-n-Propyl-1-isobutyl-n-butylamine

1-n-Propyl-1-tert-butyl-n-butylamine

1,1-Di-n-propyl-2-propyn-1-ylamine

1,1-Diethyl-2- pentyn-1-ylamine

1,1-Di-n-propyl-2-pentyn-1-ylamine

1,1-Di-n-propyl-3-butyn-1-ylamine

1,1-Diethyl-2-penten-1-ylamine

1,1-di-n-propyl-2-penten-1-ylamine

and the pharmaceutically acceptable acid addition salts of each of thesenew methylamine derivatives, together with the acid fumarate of1,1-di-n-propyl-n-butylamine.

There are, however, a certain number of the compounds of the inventionwhich are already known. In this connection may be cited, for example:

1,1-Di-(2-propen-1-yl)-3-buten-1-ylamine

or triallylmethylamine, 1,1-diallyl-n-butylamine and1,1-diallyl-n-pentylamine which are described in the J. Amer. Chem.Soc., 65, 87 (1943)

1,1,3,3-Tetramethyl-n-butylamine published in the J. Amer. Chem. Soc.,70, 4048 (1948)

1-Methyl-1-ethyl-2-pentyn-1-ylamine

1-Methyl-1-ethyl-2-heptyn-1-ylamine

1-Methyl-1-ethyl-n-pentylamine

1-Methyl-1-ethyl-n-propylamine

1-Methyl-1-ethyl-2-propen-1-ylamine

all of which are described in the J. Amer. Chem. Soc., 75, 4297 (1953)

1,1-Diethyl-2-propyn-1-ylamine

1,1-Dimethyl-2-propyn-1-ylamine

1,1-Diethyl-n-propylamine

which are already on the market.

However, as far as is known, no therapeutic activity has ever beenattributed to these known compounds.

Similarly, Tri-n-propylmethylamine or 1,1-di-n-propyl-n-butylamine, andTri-n-butylamine or 1,1-di-n-butyl-n-pentylamine have been described bySPERBER et al. in the J. Amer. Chem. Soc., 71, 3352 (1949), where theyare presented as being "less spasmolytic and more toxic than thecorresponding trialkylethylamines". Here it is more a question of amusculotropic antispasmodic activity as pointed out in the reference inquestion.

Independently of the fact that the information supplied in thispublication concerning these two compounds of formula I are completelylacking in precision, there is nothing in this test which could evenremotely suggest the activities which, in the light of the presentinvention, can be attributed to the compounds of formula I in generaland to tri-n-propyl-and tri-n-butyl-methylamines in particular.

The publication relating to the spasmolytic activity thus attributed tothe two methylamine derivatives in question does not, in fact, give anydetails as regards degree of activity nor does it make any allusion tothe method by which the spasmolytic activity was demonstrated.Furthermore, no toxicity data given. The pharmacological informationpublished by SPERBER et al. is therefore too vague to enable anyone todeduce that tri-n-propyl and tri-n-butyl methylamines have sufficientspasmolytic activity at non-toxic doses to make them likely to be of useas therapeutic agents.

In the course of the pharmacological trials carried out with thecompounds of formula I, the spasmolytic activity oftri-n-propylmethylamine or 1,1-di-n-propyl-n-butylamine was investigated"in vitro". In full agreement with the findings of SPERBER et al., itwas observed that the spasmolytic activity of this compound is veryweak, in fact practically non-existent since it is 20,000 to 25,000times weaker than that of atropine. From this it may be reasonablydeduced that the spasmolytic activity of tri-n-propylmethylamine shouldbe exerted "in vivo" at doses which are extremely toxic.

Pharmacological trials carried out "in vivo" have, in fact, shown thatat the doses at which tri-n-propylmethylamine can be used againstParkinson's disease and as an agent for correcting the extra-pyramidaldisturbances provoked by neuroleptics, i.e. at doses well below thetoxic dose, the spasmolytic activity of this compound is non-existent.

The compounds of formula I in which R₁ and R₃ each represent an atom ofhydrogen or an alkyl, alkenyl or alkynyl radical and R₂ represents analkyl radical, an alkenyl radical other than CH=CH--R₄ or an alkynylradical other than C.tbd.C--R₄, may be prepared by treating, in anappropriate medium, with a strong acid such as, for example,hydrochloric or sulphuric acid, an isocyanate or a N-formyl amine of thegeneral formula: ##STR3## wherein R₁, R₂ and R₃ have the above meaningsand A represents the group N=C=O or ##STR4## to form the corrrespondingacid addition salt of the required compound of formula I which, ifdesired, may be reacted with a base such as, for example, sodiumhydroxide to obtain the compound of formula I in the form of its freebase which may then be reacted with an organic or inorganic acid to givea different pharmaceutically acceptable acid addition salt.

The treatment of the compound of formula II with the acid may be carriedout by utilizing the reagents involved at a temperature between 15° Cand 100° C, and preferably between 50° C and 90° C.

The compounds of formula I in which R₁ and R₃ each represent an alkylradical containing from 1 to 3 atoms of carbon or an alkenyl or alkynylradical containing 2 or 3 atoms of carbon and R₂ represents the radicalCH₂ --R₅ in which R₅ represents an alkyl radical containing from 1 to 3carbon atoms or an alkenyl or alkynyl radical having 2 or 3 atoms ofcarbon, R₁, R₃ and R₅ being identical, can also be prepared by heating,in an anhydrous ether, such as for example ethyl ether, a nitrile of thegeneral formula:

    R.sub.5 --CH.sub.2 --CN                                    III

in which R₅ has the above meaning with an organo-magnesium derivative ofthe general formula:

    R.sub.5 --CH.sub.2 MgX                                     IV

in which R₅ has the same meaning as above and X represents an atom ofchlorine, bromine or iodine, and hydrolyzing the complex thus formed toobtain the desired compound of formula I which may then be reacted withan organic or inorganic acid to provide a pharmaceutically acceptableacid addition salt of the said compound.

As hydrolyzing agent, use may be made, for example, of a saturatedsolution of ammonium chloride.

The compounds of formula I in which R₁ and R₃ each represent an atom ofhydrogen or an alkyl radical and R₂ represents an alkynyl radical of theformula C.tbd.C--R₄ in which R₄ represents hydrogen, i.e. an ethynylradical, may be prepared in liquid ammonia by reacting sodium amide anda halide of the general formula: ##STR5## in which R₁ and R₃ have themeaning given above and Hal represents an atom of chlorine or bromine togive the desired compound of formula I which may then be reacted with anorganic or inorganic acid to provide a pharmaceutically acceptable acidaddition salt of the said compound.

The compounds of formula I in which R₁ and R₃ each represent an atom ofhydrogen or an alkyl radical and R₂ represents an alkynyl radical of theformula C.tbd.C--R₄ in which R₄ represents an alkyl radical containingfrom 1 to 5 atoms of carbon may be prepared by reacting a metallicderivative of the general formula: ##STR6## in which Me represents anatom of alkali metal such as, for example, sodium and R₁ and R₃ have themeaning given above with a halide of the formula:

    R.sub.4 -- Hal                                             VII

in which R₄ has the meaning given above and Hal has the same meaning asin formula V to obtain the required compound of formula I which may thenbe reacted with an organic or inorganic acid to provide apharmaceutically acceptable acid addition salt of the said compound.

The compounds of formula I in which R₁ and R₃ each represent an atom ofhydrogen or an alkyl radical and R₂ represents an alkenyl radical of theformula CH=CH--R₄ in which R₄ has the same meaning as in the definitionof formula I may be prepared by hydrogenating in an appropriate solventsuch as, for example, heptane, and in the presence of a Lindlarcatalyst, an amine of the general formula: ##STR7## in which, R₁, R₃ andR₄ have the meaning given above, to provide the required compound offormula I which may then be reacted with an organic or inorganic acid toobtain a pharmaceutically acceptable acid addition salt of the saidcompound.

The operation of hydrogenation is preferably carried out at atemperature between 30° C and 60° C and generally at about 50° C.

The compounds of formula II may be prepared in various ways, namely:

a. when A represents the radical N=C=O: either by reacting an acetamidederivative of the general formula: ##STR8## in which R₁, R₂ and R₃ havethe same meaning as in formula II with chlorine or bromine in analkaline medium such as, for example, in an aqueous solution of sodiumor potassium hydroxide, or by reacting an acetic acid derivative of thegeneral formula: ##STR9## in which R₁, R₂ and R₃ have the same meaningas in the compounds of formula II above with a chlorinating agent suchas, for example, thionyl or oxalyl chloride, to obtain the correspondingacyl chloride which is then treated with an alkali metal azide such as,for example, sodium azide, which provides the required compound offormula II, or following another process, by heating a compound offormula X directly with hydrogen azide in an acid medium, for example,sulphuric acid, to obtain the desired compound of formula II.

In this latter case, the isocyanate thus formed is immediately convertedby hydrolysis to the corresponding amine of formula I

b. When A represents the radical ##STR10## by heating a tertiary alcoholof the general formula: ##STR11## in which R₁, R₂ and R₃ have the samemeaning as that given for the above compounds of formula II, with analkaline cyanide such as, for example, sodium or potassium cyanide inthe presence of an acid such as, for example, sulphuric acid.

The compounds of formula IX can be obtained by reacting anhydrousammonia with the corresponding acids of formula X or preferably with thehalides of these acids. The acids can be prepared from the alcohols offormula XI and formic acid in a sulphuric acid medium.

The compounds of formula XI are either known compounds or can beprepared in accordance with known procedures such as, for example, byreacting an organo-lithium compound with an appropriate ketone in ananhydrous ether medium such as, for example, tetrahydrofuran.

The compounds of formula V are either known products or can be preparedby the method described in the J. Org. Chem. 1961, 26, 725, i.e. bytreating a 1,1-dialkyl-1-ethynyl-carbinol with cuprous chloride andhydrochloric acid in the presence of copper-bronze powder and calciumchloride. The 1,1-dialkyl-1-ethynyl-carbinols mentioned above are eitherknown products, having been described in the Annales de Chimie, 1924,10, (I), p 366, or can be prepared by known procedures described, forexample, in Organic Syntheses Collective, Vol. III, p 416. The productsof formula VI may be prepared in liquid ammonia through the action of analkali metal such as, for example, sodium, on the corresponding1,1-dialkyl-1-ethynyl-methylamine which is, in fact, a compound coveredby formula I. The compounds of formula VIII are also included within thescope of formula I.

It has been discovered that the methylamine derivatives of formula Ipossess valuable pharmacological properties which are likely to renderthem useful in human and veterinary therapy.

In particular, it has been found that the compounds of the inventionpresent central noradrenergic and central dopaminergic properties. Theselatter properties manifest themselves by an inhibitory action onreserpine-induced and neuroleptic-induced catatonia and catalepsy.

Pharmacological trials performed with the compounds of the inventionhave shown that tri-n-propylmethylamine hydrochloride or1,1-di-n-propyl-n-butylamine hydrochloride possesses a marked degree ofactivity. However, it was surprisingly and quite unexpectedly, observedthat 1,1-di-n-propyl-n-butylamine acid fumarate presents a degree ofactivity which is even markedly greater than that of the correspondinghydrochloride It was, in fact, observed that1,1-di-n-propyl-n-butylamine acid fumarate is from 20 to 40 times moreactive than the corresponding hydrochloride in tests involvingreserpine-induced and neuroleptic-induced catatonia.

Furthermore, at doses which completely suppress neuroleptic-inducedcatatonia and catalepsy, it was observed that the compounds of theinvention do not influence the anti-amphetamine effects or theneuroleptics in the rat and their anti-apomorphine effects in the dog.Furthermore, the compounds of the invention have no emetic action in thedog at any doses and are not cholinolytic agents.

These pharmacological properties taken as a whole are likely to renderthe compounds of formula I useful in treating Parkinson's disease aswell as for correcting extra-pyramidal disturbances provoked byneuroleptics.

Parkison's disease is a chronic and progressive affection characterizedin particular by a dopamine deficiency in the thalamus and the caudateand lenticular nuclei, with akinesia, rigidity and tremor as visiblesymptoms.

Many active drugs have already been proposed for combating Parkinson'ssyndrome. Most of these products are central anti-cholinergic agentswith peripheral anti-cholinergic effects. These compounds are of naturalorigin, such as, for example atropine or are obtained synthetically as,for example, diethazine, benztropine or trihexyphenidyl.

However, these drugs may present undesirable side-effects, due in mostcases to their peripheral anti-cholinergic properties, such side-effectstaking the form, for example, of dryness of the mouth, difficulty inoptical accommodation, tachycardia, constipation and retention of urine.These products will thus be contraindicated in cases of glaucoma andhypertrophy of the prostate.

L-Dopa or levodopa, a precursor or dopamine, has also been proposed inparkingsonism. However, in view of its partial destruction in thedigestive system, L-dopa must be administered at very high doses, whichvery often induce undesireable side-effects. The most serious of theseside-effects are cardiovascular in nature and in particular take theform of disturbances of cardiac rhythm and orthostatic hypotension.Patients treated with L-dopa must, therefore, not presentcontraindications on the cardiac plane.

Recently, amantadine i.e. 1-amino-adamantane has been proposed forantiparkinsonian therapy. This product, which stimulates the liberationof dopamine is very active but produces several undesirable side-effectsand also decreases in activity after a certain length of time.

For this reason, it is very difficult for the doctor to select amongstthe various antiparkinsonian drugs, that which will be effective for thecase under treatment. Each patient must be considered as an individualcase. All the known methods of treating Parkinson's disease aresymptomatic and, in spite of the medication used, the disease continuesto progress. The treatment of parkinsonism requires the successive useof one or more therapeutic substances and it is often necessary toinstitute therapeutic cycles. Frequently, two antiparkinsonian agentsmust be simultaneaously administered, the first being considered as thebasic drug and the second as an auxiliary or additional drug.Furthermore, since treatment is of long duration the alternating use ofdifferent products is necessary.

The search for new antiparkinsonian agents is therefore of primaryimportance. From this point of view, the compounds of formula I willconstitute valuable additions to antiparkinsonian therapy, since atpresent there is no ideal agent for the treatment of this disease asexplained in detail hereabove.

The compounds of the invention will consequently constitute valuableadditions to the therapeutic arsenal at the disposal of the doctor andwill provide useful replacement medication for any drug which has becomeineffective for any reason such as a change in the state of the patientor habituation.

Although the pharmacological spectrum of the compounds of the inventionis very similar to that of amantadine, pharmacological trials performedwith the compounds of formula I have revealed marked differences incomparison with amantadine. For example, when comparing the doses of thecompounds of the invention and of amantadine which have a certain degreeof activity, it has been observed that the active dose in question isalways proportionally farther from the toxic dose in the case of thecompounds of the invention than in the case of amantadine. In otherwords, the safety margin offered by the compounds of the invention issuperior to that of amantadine. Other differences which are particularlyevident have been observed with the preferred compound of the invention,namely:

tri-n-propylmethylamine or 1,1-di-n-propyl-n-butylamine in basic form orin the form of a pharmaceutically acceptable acid addition salt such asthe hydrochloride or the acid fumarate.

For example, on the cardiovascular plane, it has been observed that thepreferred compound of the invention does not cause any undesirableeffect on the electrocardiogram whereas a dose of 5 mg/kg of amantadineinjected into the dog provokes cardiac arrhythmia due to ventricularextrasystoles. It has also been found that the preferred compound of theinvention does not potentiate the peripheral effects of norepinephrineand is not a ganglioplegic agent while tests performed with amantadinehave demonstrated that this compound potentiates the peripheraladrenergic effects and furthermore exerts a ganglioplegic action.

The preferred compound of the invention which does not present theseundesirable side-effects observed with amantadine will not thereforeinduce cardiac disturbances or disorders of arterial pressure.

As mentioned above, certain types of antiparkinsonian agents such asdiethazine, benztropine etc. . . frequently provoke undesirableside-effects of an anti-cholinergic nature (dryness of the mouth,difficulty in optical accomodation etc. . .)

The preferred compound of the invention being diviod of anticholinergicactivity does not present these disadvantages.

Similarly, the preferred compound of the invention as it is devoid ofemetic properties and of undesirable side-effects on theelectrocardiogram, will not provoke vomiting or cardiac arrhythmia whichare two frequent side-effects of L-dopa.

Pharmacological trials have been performed with a view to determiningthe various properties of the compounds of the invention which, takentogether, are capable of rendering the said compounds useful in thetreatment of Parkinson's disease and for the correction ofextra-pyramidal disturbances induced by neuroleptics.

I. Inhibition of reserpine-induced and neuroleptic-induced catatonia(dopaminergic properties)

1. Inhibition of reserpine-induced catatonia

After sufficient doses of reserpine have been administered to the rat, aseries of symptoms occur, more particularly ptosis, catatonia and a dropin central temperature. These symptoms are caused by the depletion ofthe intragranular reserve pool of boigenetic amines at the synapticterminals.

The antidepressants of the tricyclic type as well as the inhibitors ofmonosamine oxydase (I.M.A.O.) antagonize more particularly theappearance of ptosis and the drop in central temperature. On catatonia,the action of such compounds is not non existent but is considerablyless marked.

As against this, the synthetic antiparkinsonian agents principallyinfluence catatonia while their activity on ptosis and hypothermia isnon existent or weaker.

An oral dose of the compound to be studied in aqueous solution wasadministered to batches of 10 male rats of the OFA strain weighing about150 to 200 g. Thirty minutes later a dose of 5 mg/kg of reserpine wasgiven by intraperitoneal route. Three hours after the injection ofreserpine, the animals were suspended by the four paws to a horizontallystretched wire fixed at 15 cm from the ground. The catatonic animalswere those which maintained the position so given for at least 30seconds. Each animal which maintained the position so given received thescore of 1 and those which did not maintain the said position were giventhe score of 0. The maximum score was therefore 10 per batch. Anidentical trial was undertaken with control animals which receivedreserpine but none of the compounds being studied.

The following compounds of formula I were tested in comparison withamantadine in accordance with the process indicated hereabove. Thesecompounds were preferably studied in the form of a pharmaceuticallyacceptable acid addition salt such as the hydrochloride or the fumarate.

1,1-Di-n-propyl-n-butylamine (Compound 1)

1-Ethyl-1-n-propyl-n-butylamine (Compound 2)

1-Ethyl-1-isobutyl-n-butylamine (Compound 3)

1-Ethyl-1-n-propyl-n-pentylamine (Compound 4)

1-n-Propyl-1-isobutyl-n-butylamine (Compound 5)

1,3-Dimethyl-1-n-propyl-n-pentylamine (Compound 6)

1,3-Dimethyl-1-ethyl-n-hexylamine (Compound 7)

1-Methyl-1-isobutyl-n-pentylamine (Compound 8)

1-Methyl-1-n-propyl-n-hexylamine (Compound 9)

1,1-Dimethyl-n-octylamine (Compound 10)

1,1-Di-(2-propen-1-yl)-3-buten-1-ylamine (Compound 11)

1,1-Di-n-butyl-n-pentylamine (Compound 12)

1,1,3-Trimethyl-n-heptylamine (Compound 13)

1,1-Diethyl-n-butylamine (Compound 14)

1,1-Diethyl-n-propylamine (Compound 15)

1,1-Dimethyl-n-propylamine (Compound 16)

1,1-Dimethyl-3-ethyl-n-hexylamine (Compound 17)

1,1-Diisobutyl-n-butylamine (Compound 18)

1-n-Propyl-1-isopropyl-n-butylamine (Compound 19)

1-n-Propyl-1-tert-butyl-n-butylamine (Compound 20)

1,1-Di-n-propyl-2-propyn-1-ylamine (Compound 21)

1,1-Diethyl-2-pentyn-1-ylamine (Compound 22)

1,1-Diethyl-2-penten-1-ylamine (Compound 23)

1,1-Di-n-propyl-2-pentyn-1-ylamine (Compound 24)

1,1-Di-n-propyl-2-penten-1-ylamine (Compound 25)

1,1-Di-n-propyl-3-butyn-1-ylamine (Compound 26)

The results obtained with the compounds of formula I listed hereabove aswell as with amantadine are given in Table I hereunder. These resultsare expressed in the following manner:

0 : represents 0% inhibition of catatonia in comparison with thecontrols (namely a score of 10 per studied batch).

1 : represents 20 to 30% inhibition of catatonia in comparison with thecontrols (namely a score of 7 to 8 per studied batch).

2 : represents 50% inhibition of catationia in comprison with thecontrols (namely a score of 5 per studied batch)

3 : represents 70 to 80% inhibition of catatonia in comparison with thecontrols (namely a score of 2 or 3 per studied batch).

4 : represents 100% inhibition of catatonia in comparison with thecontrols (namely a score of 0 per studied batch).

                  Table I                                                         ______________________________________                                                Dose administered                                                                            Inhibition of reserpine-                               Compound                                                                              in mg/kg       induced catatonia                                      ______________________________________                                        1       5              4                                                      2       5              1                                                      3       20             3                                                      4       20             3                                                      5       20             2                                                      6       20             1                                                      7       20             1                                                      8       20             1                                                      9       20             1                                                      10      20             1                                                      11      20             1                                                      12      20             1                                                      13      25             1                                                      14      50             3                                                      15      50             1                                                      16      50             1                                                      17      11             1                                                      18      12             2                                                      19      6              3                                                      20      6              2                                                      21      30             2                                                      22      60             1                                                      23      60             1                                                      24      20             1                                                      25      6              3                                                      26      30             1                                                      Amantadine                                                                            100            4                                                      ______________________________________                                    

These results show that Compound 1 which is the preferred compound ofthe invention is as active as amantadine but at a dose which is twentytimes inferior to that of amantadine.

2. Inhibition of neuroleptic-induced catatonia

The blocking of dopaminergic receptors by neuroleptics in theextra-pyramidal system induces catatonia in the rat. Catatonia isdifferentiated from sedative properties by means of the test usedhereabove for reserpine-induced catatonia. The same system of scoringwas also employed in the present case.

An oral dose of the compound to be studied in aqueous solution wasadministered to batches of 10 male rats of the OFA strain weighing about150 to 200 g. Thirty minutes later a dose of 12.5 mg/kg ofprochlorperazine was given by intraperitoneal route. Three hours afterthe injection of this latter compound, catatonia was measured. Anidentical trial was also carried out with control animals which receivedprochlorperazine but none of the compounds under study.

The results obtained with the above listed compounds in comparison withamantadine are set out in the following Table II. The scoring system,used was that given hereabove in Table I.

                  Table II                                                        ______________________________________                                                Dose administered                                                                            Inhibition of the neuro-                               Compound                                                                              in mg/kg       leptic-induced catatonia                               ______________________________________                                        1       5              4                                                      2       5              1                                                      3       20             3                                                      4       20             3                                                      5       20             4                                                      6       20             1                                                      7       40             1                                                      8       50             4                                                      9       20             1                                                      10      50             1                                                      11      20             1                                                      12      20             1                                                      13      50             1                                                      14      50             3                                                      15      50             3                                                      16      10             1                                                      17      11             2                                                      18      12             1                                                      19      6              3                                                      20      50             1                                                      21      30             1                                                      22      30             1                                                      23      30             1                                                      24      20             2                                                      25      6              3                                                      26      30             4                                                      Amantadine                                                                            100            4                                                      ______________________________________                                    

These results show that Compound 1 is also twenty times more active thanamantadine in this test and that Compound 5 is five times more activethan amantadine while Compound 8 is twice as active.

Furthermore Compound 1 at a dose as low as 1 mg/kg, provokes a 70%inhibition of the neuroleptic-induced catatonia.

The results mentioned in the above Tables I and II in connection withCompound 1 were obtained with 1,1-di-n-propyl-n-butylamine in the formof its hydrochloride. In the form of its acid fumarate,1,1-di-n-propyl-n-butylamine is from 20 to 40 times more active aspreviously indicated. For example, a score of 4 was obtained in thetests involving reserpine-induced and neuroleptic-induced catatonia asdescribed hereabove with only 3 mg/kg of 1,1-di-n-propyl-n-butylamineacid fumarate.

II. Acute toxicity

In the acute toxicity test the LD₅₀ was determined on mice by oral routeusing the method of LICHFIELD and WILCOXON (J. Pharmacol. 1938, 2,192-216). The compounds were administered in aqueous solution and theperiod of observation was 10 days after administration of the compoundunder study.

The following results were recorded in comparison with amantadine.

    ______________________________________                                        Compound         LD.sub.50 (in mg/kg)                                         ______________________________________                                        1                 100                                                         2                 150                                                         6                >500                                                         9                1750                                                         12                500                                                         Amantadine       1050                                                         ______________________________________                                    

These results show that compounds of the invention are generally moretoxic than amantadine. However, when a comparison is made between theLD₅₀ given hereabove and the effective dose to obtain inhibition ofreserpine-induced or neuroleptic -induced catatonia, it is seen thatsuch comparisons are always more favourable to the compounds of theinvention than to amantadine. The index (LD₅₀ /ED₂₀₋₃₀) was determined.In this index, ED₂₀₋₃₀ represents the effective dose to obtain 20 to 30%inhibition of the catatonia, this value being represented by the FIG. 1in Tables I and II.

The following results were registered:

    ______________________________________                                        Compound         Index                                                        ______________________________________                                        2                25                                                           6                >25                                                          9                87                                                           12               25                                                           ______________________________________                                    

The corresponding index for amantadine is 1050/50 = 21, which shows thatthe compounds of the invention present greater advantages thanamantadine.

Similarly, an index LD₅₀ /ED₁₀₀ was determined, ED₁₀₀ representing theeffective dose to obtain 100% inhibition of the catatonia.

This latter value is represented in Tables I and II by the FIG. 4.

The following results were recorded:

    ______________________________________                                        Compound         Index                                                        ______________________________________                                        1                20                                                           Amantadine       10                                                           ______________________________________                                    

These figures show that Compound 1 presents a total inhibitory action onreserpine-induced and neuroleptic-induced catatonia at a dose which isproportionally twice as far from the toxic dose as in the case ofamantadine. Compound 1 possesses, consequently, a higher safety marginthan that of amantadine.

In the case of 1,1-di-n-propyl-n-butylamine acid fumarate, the activedose is still farther removed from the toxic dose than in the case ofCompound 1 as the corresponding index is 100/3≳33.

Additional trials were carried out on rats with Compound 1 andamantadine. These trials involved catalepsy as evidenced by the crossingof the animals' homolateral paws. It was observed in these trials that 5mg/kg of Compound 1 when administered by oral route 30 minutes before anintraperitoneal injection of prochlorperazine provoked completeinhibition of the catalepsy 3 hours after the injection of this lattersubstance. With regard to amantadine, a dose of 80 mg/kg was necessaryto induce complete inhibition of the catalepsy.

The efficacy of Compound 1 in curative treatment was also demonstrated.

a. Suppression of reserpine-induced catatonia

Batches of 5 male rats of the OFA strain, weighing 150 to 200 g weregiven 5 mg/kg of reserpine by intraperitoneal route. One hour and 45minutes later, namely when the animals were in a state of catatonia, anaqueous dose of the compound to be studied was administered by oralroute to all the animals with the exception of the control group.

The progress of the catatonia was then noted following the scale used inthe tests described hereabove.

The maximum score was thus 5 per batch which means that all the animalsof the batch were considered to be still in a state of catatonia.

The following results were obtained with Compound 1 in comparison withamantadine:

                  Table III                                                       ______________________________________                                               Time after administration of reserpine                                        2h   2h15    2h30    3h   3h30  4h   5h                                ______________________________________                                        Controls 5      5       5     3    3     1    2                               Compound 1                                                                             4      3       2     0    0     0    0                               2.5 mg/kg                                                                     Compound 1                                                                             5      1       0     0    0     0    0                                5 mg/kg                                                                      Amantadine                                                                             5      4       3     2    1     0    0                                80 mg/kg                                                                     ______________________________________                                    

These figures show that at doses of 2.5 mg/kg and 5 mg/kg, by oralroute, Compound 1 suppresses reserpine-induced catatonia more rapidlythan a dose of 80 mg/kg of amantadine administered under the sameconditions.

Compound 1 is thus at least 32 times more active than amantadine withrespect to reserpine-induced catatonia in curative treatment.

b. Suppression of neuroleptic-induced catatonia

Batches of 5 male rats of the OFA strain were given 12.5 mg/kg ofprochlorperazine by intraperitoneal route. Fifty-five minutes later, anoral dose in aqueous solution of the compound to be studied wasadministered to all the animals with the exception of the control group.The progress of the catatonia was noted following the same scale as thatused in the tests described above.

The following results were registered with Compound 1 as well as withamantadine:

                  Table IV                                                        ______________________________________                                               Time after administration of prochlorperazine                                 1h30  2h30    3h      3h30  4h    5h                                   ______________________________________                                        Controls 4       4       4     3     1     1                                  Compound 1                                                                             3       0       0     0     0     0                                   5 mg/kg                                                                      Amantadine                                                                             5       2       1     0     0     0                                  80 mg/kg                                                                      ______________________________________                                    

These results show that under the conditions of curative treatment, adose of 5 mg/kg of Compound 1 acts against neuroleptic-induced catatoniamore rapidly than does a dose of 80 mg/kg of amantadine administeredunder the same conditions. In this test, Compound 1 is consequently atleast 16 times more active than amantadine.

The toxico-pharmacological index, LD₅₀ /ED₅₀, is again more favourableto Compound 1 than to amantadine, i.e. 20 for Compound 1 and only 13 foramantadine.

A test was also carried out in order to determine whether Compound 1possessed cholinolytic properties.

For this purpose, the MAGNUS test (Arch. gen. Physio. 1904, 102) wasused. This test consists in determining the dose of acetylcholine which,when added to the bath, provokes spasm of the isolated duodenum of therat. The next step consists in determining the dose of the compoundunder study which, when added to the bath 30 seconds before theacetylcholine, reduces the spasm.

The following results were recorded with Compound 1 in comparison withatropine:

                  Table V                                                         ______________________________________                                                  Doses in g/ml                                                                             % of inhibition                                                   of bath     of the spasm                                            ______________________________________                                        Acetylcholine                                                                             0.5 × 10.sup.-5                                                                       --                                                  Atropine    0.1 × 10.sup.-6                                                                        45                                                             0.2 × 10.sup.-6                                                                       100                                                 Compound 1  0.2 × 10.sup.-6                                                                       0                                                               0.1 × 10.sup.-5                                                                       0                                                               0.1 × 10.sup.-4                                                                       0                                                               0.1 × 10.sup.-3                                                                       0                                                               0.2 × 10.sup.-2                                                                        36                                                             0.5 × 10.sup.-2                                                                        60                                                 ______________________________________                                    

These results show that Compound 1 is 20,000 to 25,000 times less activethan atropine.

The cholinolytic activity "in vitro" of Compound 1 may thus beconsidered as virtually non-existent in comparison with that ofatropine.

The extremely weak cholinolytic action of Compound 1 must necessarilyoccur at toxic doses.

The absence of cholinolytic properties of Compound 1 was verified "invivo" at therapeutic doses.

For this purpose, the following test was performed with a view todetermining the anti-tremorine properties of Compound 1.

When injected into mice, tremorine produces peripheral effects i.e.weeping, sweating, salivation and diarrhoea and central effects i.e.tremor and akinesia. Such effects are due to an increase in the amountof intracerebral acetylcholine and serotonine.

Male mice of the OF₁ strain weighing about 22 g were divided intobatches of 10. Each batch received, by oral route, 50 mg/kg of thecompound to be tested in aqueous solution. Thirty minutes later a doseof 10 mg/kg of tremorine was injected by intraperitoneal route and, atdifferent times after this injection, note was taken of the cholinergiceffects on each animal in accordance with the following scale:

0 : no action

1 : slight action

2 : average action

3 : strong action

4 : very strong action

The results obtained with 5 mg/kg of Compound 1 and 40 mg/kg ofamantadine were as follows:

With respect to the peripheral cholinergic effects i.e. salivation,sweating, and weeping, a score of 4 was registered for the controlanimals, 20, 30 and 40 minutes after the injection of tremorine for both5 mg/kg of Compound 1 and 40 mg/kg of amantadine. Identical results wereobtained with respect to the central cholinergic effects i.e. normal andprovoked tremor.

These results show that Compound 1 and amantadine are devoid ofantitremorine properties, which confirms the absence of cholinolyticproperties in the case of Compound 1 at therapeutic doses.

Tests were also carried out with Compound 1 with a view to studying theinfluence of this compound on peripheral noradrenergic phenomena.

The following test was performed for this purpose:

A cat, anaesthetized with pentobarbital, received a sufficient dose ofnorepinephrine to increase arterial pressure but not sufficient to causecontraction of the nictitating membrane. Arterial pressure was measuredat the carotid immediately after administration of the dose ofnorepinephrine. After this, increasing doses of Compound 1 in aqueoussolution were administered by intravenous route every 30 minutes. Aftereach dose of Compound 1, a further dose of norepinephrine was given andthe following parameters were recorded: the increase in arterialpressure, the contractile reaction of the nictitating membrane due toexogenous norepinephrine as well as the contractile reaction of thismembrane induced by the release of norepinephrine provoked by thesub-maximum electric stimulation of the cervical sympathetic nerve.

The results listed hereunder were recorded with Compound 1 andamantadine:

                  Table VI                                                        ______________________________________                                                     Increase in Contractile reaction                                              arterial    of the nictitating                                   Cumula-      pressure in membrane (in mm*)                                    tive         mm Hg after Without   With                                       doses        injection of                                                                              electric  electric                                   in mg/kg     norepinephrine                                                                            stimulation                                                                             stimulation                                ______________________________________                                        Compound                                                                              0        26          0       17                                       1       0.1      18          0       15                                               1        25          0       16                                               3        29          0       17                                               5        25          0       16                                               10       22          0       12                                       Amanta- 0        28          0       20                                       dine    0.1      29          0       20                                               1        35          3       20                                               3        35          4.4     16                                               5        59          5.9     10                                               10       57          7.5      4                                       ______________________________________                                         *The mm express the elevation of the contraction registered on a graph.  

These results show that Compound 1 does not potentiate the effectseither of exogenous norepinephrine or of endogenous norepinephrine.

Amantadine, on the other hand, potentiates exogenous norepinephrine from1 mg/kg, since it increases the intensity and duration of thehypertensive effects of this amine and, after it has been administered,a dose of norepinephrine which would otherwise have no effect on themembrane provokes, on the contrary, a contractile reaction on the partof the latter.

Furthermore, amantadine itself stimulates the contractile reaction ofthe nictitating membrane but does not potentiate the effects of theelectric stimulation. On the contrary, amantadine shows ganglioplegicproperties from 5 mg/kg.

It will be appreciated that for therapeutic use the compounds of theinvention will normally be administered in the form of a pharmaceuticalor veterinary composition in a dosage unit form appropriate to therequired mode of administration, the composition comprising as activeingredient a compound of the invention in association with apharmaceutical carrier or excipient therefor. For oral administration,the composition may take the form of, for example, a coated or uncoatedtablet, a hard- or soft-gelatin capsule, a suspension or a syrup. Thecomposition may alternatively take the form of a suppository for rectaladministration, or of a solution or suspension for parenteraladministration.

When in dosage unit form the composition may contain from 5 to 50 mg,preferably from 5 to 10 mg of the active ingredient per dosage unit fororal administration, from 5 to 50 mg of the active ingredient per dosageunit for rectal administration, or from 1 to 10 mg of the activeingredient per dosage unit for parenteral administration.

The therapeutic compositions of the invention will be prepared byassociating at least one of the compounds of formula I or apharmaceutically acceptable acid addition salt thereof with at least oneappropriate carrier or excipient therefor. Examples of suitable carriersor excipients are talc, magnesium stearate, milk sugar, saccharose,carboxymethylcellulose, starches, kaolin, levilite and cocoa butter.

The following Examples illustrate the preparation of the compounds ofthe invention together with a suitable therapeutic composition:

EXAMPLE 1 Preparation of 1,1-di-n-butylamine hydrochloride ortri-n-propyl-methylamine hydrochloride.

a. 1,1-Di-n-propyl-n-butylisocyanate

In a 2-liter three-necked flask fitted with a water condenser, amechanical stirrer, a thermometer and a dropping-funnel were placed 144g of sodium hydroxide in tablet form and 1200 ml of water. The solutionwas cooled to 5° C and, under stirring, 48 ml of bromine were slowlyadded. The operation of adding the bromine lasted two hours and then, ata temperature of 0° C, 111 g of 2,2-di-n-propyl-valeramide were added tothe yellowish-green solution. Stirring of the mixture was maintained atabout 0° C for 4 hours. The oily phase was then extracted with threefractions of ether each of 300 ml and the ethereal phase was washedtwice with 100 ml of water, dried over magnesium sulphate and evaporatedunder vacuum. The light yellow oil so obtained was distilled underreduced pressure of 5 mmHg.

In this manner 105 g of colourless 1,1-di-n-propyl-n-butyl-isocyanatewere obtained.

B.P. 78°-79° C under 5mmHg.

Yield: 95%

By following the same procedure as that described hereabove but usingthe appropriate starting-products, the compounds hereunder wereprepared:

    ______________________________________                                        Compounds               Boiling point ° C                              ______________________________________                                        1,1-Di-n-butyl-n-pentylisocyanate                                                                     92-93                                                                         (0.5 mmHg)                                            (Yield: 80%)                                                                  1-n-Propyl-1-isopropyl-n-butylisocyanate                                                              97                                                                            (15 mmHg)                                             ______________________________________                                    

b. 1,1-Di-n-propyl-n-butylamine hydrochloride

Into a three-necked flask equipped with a mechanical stirrer, adropping-funnel, a thermometer and a condenser, were introduced 200 mlof water and 90 ml of concentrated hydrochloric acid (d=1.19). The acidsolution was heated to 90° C and then, under vigorous stirring, 105 g of1,1-di-n-propyl-n-butylisocyanate, prepared as previously described,were slowly added. The operation of addition lasted one hour after whichthe reaction medium was heated for a further 4 hours at a temperaturebetween about 95° and 100° C. The mixture was then cooled to about 0° Cand the colourless crystals so obtained were filtered off dried byexposure to the air and then in a dessicator in the presence ofpotassium hydroxide. In this manner, 99 g of1,1-di-n-propyl-n-butylamine hydrochloride were isolated in the form ofa white crystalline powder.

The product does not melt but sublimates from 220° C.

Yield: 90%

By following the same procedure as that described hereabove but usingthe appropriate starting-products, the compounds hereunder wereobtained:

    __________________________________________________________________________    Compound                                                                      __________________________________________________________________________    1,1-Di-n-butyl-n-pentylamine hydrochloride                                                               M.P. 68.1° C                                (Yield : 63%)                                                                 1-Ethyl-1-n-propyl-n-butylamine hydrochloride                                                            180° C                                                                 (sublimation)                                      1-Ethyl-1-isobutyl-n-butylamine hydrochloride                                                            230° C                                                                 (sublimation)                                      1-n-Propyl-1-isobutyl-n-butylamine hydrochloride                                                         M.P. 260° C                                 1-Ethyl-1-n-propyl-n-pentylamine hydrochloride                                                           M.P. 230° C                                                            (decomposition)                                    1-n-Propyl-1-isopropyl-n-butylamine hydrochloride                                                        M.P. 260° C                                                            (decomposition)                                    __________________________________________________________________________

EXAMPLE 2 Preparation of 1,1-di-n-propyl-n-butylamine acid fumarate

To a solution of 1.16 g (0.01 mol) of fumaric acid in 20 ml of acetone,were slowly added 1.57 g (0.01 mol) of 1,1-di-n-propyl-n-butylamine(n_(D) ²¹ = 1.4349) dissolved in 10 ml of acetone, this amine havingbeing prepared from its hydrochloride and a 30% aqueous solution ofsodium hydroxide. The mixture was stirred for one hour and then thecrystals which formed were suction-filtered, washed with acetone anddried under vacuum.

In this manner, 1,1-di-n-propyl-n-butylamine acid fumarate was obtainedin the form of a white powder.

M.P. 216° C with sublimation

Yield: 100%

EXAMPLE 3 Preparation of 1-n-propyl-1-isobutyl-n-butylaminehydrochloride

a. 1-n-Propyl-1-isobutyl-n-butanol

Into a 250 ml three-necked flask equipped with a mechanical stirrer anitrogen inlet, a dropping-funnel and a thermometer, were introducedunder nitrogen atmosphere 2.8 g (0.2 mol) of lithium in small portionsand 100 ml of anhydrous and purified tetrahydrofuran. The suspension oflithium in tetrahydrofuran was cooled to -20° C and then while stirringa mixture of 22.8 g (0.2 mol) of di-n-propylketone and 30 g (0.2 molplus a 10% excess) of isobutyl bromide were slowly added. The operationof addition lasted about 3 hours during which time a temperature ofabout -20° C was maintained. The solution was allowed to stand for about12 hours at room temperature and then concentrated. The oil so obtainedwas taken up in water, extracted with ether and distilled under reducedpressure.

In this manner, 21 g of 1-n-propyl-1-isobutyl-n-butanol were obtained inthe form of a clear liquid which was slightly yellow.

B.P. 74°-76° C under 5 mmHg.

Yield: about 60%

Following the same procedure as that described above but using theappropriate starting-products, the compounds listed hereunder wereprepared:

    ______________________________________                                        Compound              Boiling point ° C                                ______________________________________                                        1,1-Diethyl-n-butanol 62                                                                            (15 mmHg)                                               (Yield : 50%)                                                                 1-Ethyl-1-n-propyl-n-butanol                                                                        178-179                                                 (Yield : 35%)         (760 mmHg)                                              1-Ethyl-1-isobutyl-n-butanol                                                                        78-79                                                   (Yield : 40%)         (15 mmHg)                                               1,1-Di-n-propyl-n-butanol                                                                           78-80                                                   (Yield : 60%)         (0.15 mmHg)                                             1-n-Propyl-1-isopropyl-n-butanol                                                                    81                                                                            (15 mmHg)                                               1-n-Propyl-1-tert-butyl-n-butanol                                                                   90-92                                                                         (14 mmHg)                                               1,1-Dimethyl-n-octanol                                                                              93-95                                                   (Yield : 45%)         (13 mmHg)                                               1,1,3-Trimethyl-n-heptanol                                                                          Decomposition                                           (Yield : 60%)                                                                 1,1-Dimethyl-3-ethyl-n-hexanol                                                                      Decomposition                                           (Yield : 30%)                                                                 1,3-Dimethyl-1-ethyl-n-hexanol                                                                      Decomposition                                           (Yield : 35%)                                                                 1,3-Dimethyl-1-n-propyl-n-pentanol                                                                  Decomposition                                           (Yield : 46%)                                                                 1-Methyl-1-isobutyl-n-pentanol                                                                      Decomposition                                           (Yield: 33%)                                                                  1-Methyl-1-n-propyl-n-hexanol                                                                       Decomposition                                           (Yield : 30%)                                                                 1,1-Diisobutyl-n-butanol                                                                            75-76                                                   (Yield : 60%)         (4 mmHg)                                                1-Ethyl-1-n-propyl-n-pentanol                                                                       87                                                      (Yield: 35%)          (11 mmHg)                                               ______________________________________                                    

b. 1-n-Propyl-1-isobutyl-n-butylamine hydrochloride

Into a 250 ml three-necked flask equipped with a mechanical stirrer, adropping-funnel, a condenser and a dip thermometer, were introduced 6.5g (0.1 mol) of dry potassium cyanide in powder form, 14.4 g (0.083 mol)of 1-n-propyl-1-isobutyl-n-butanol and 12 ml of acetic acid. Whilestirring, a mixture of 25 g of concentrated sulphuric acid (d= 1.83) and12 ml of acetic acid was slowly added. The operation of addition lastedabout 2 hours during which time a temperature of about 50° C wasmaintained. The reaction mixture was heated to 70° C for 2 hours and wasthen slowly poured into 100 ml of ice water. After this, it wasneutralized with a 20% aqueous solution of sodium hydroxide andextracted with ether. The ether was evaporated out and an oil comprisingN-formylated 1-n-propyl-1-isobutyl-n-butylamine was collected.

The N-formylated amine thus obtained was refluxed for 2 hours in thepresence of 20 ml of concentrated hydrochloric acid. While cooling, thehydrochloride of this amine crystallized. It was then filtered off andwashed with acetone.

In this manner, 11 g of 1-n-propyl-1-isobutyl-n-butylamine hydrochloridewas collected in the form of a white powder.

M.P.>260° C with temperature decomposition without melting at about 280°C.

Yield: 64%

In a thin layer chromatographic assay performed on silicagel plates(Merck HF 254) using a system of solvents comprising 79 parts ofbenzene, 14 parts of methanol and 7 parts of acetic acid and with iodineas revealing agent, a Rf of 0.6 was recorded.

Following the same procedure as that described hereabove but using theappropriate starting-products, the compounds listed hereunder wereprepared. The Rf value given for each of these compounds was determinedin a thin layer chromatographic assay using the same support, the samesystem of solvents and the same revealing agent as those maintained inthe Example hereabove described:

    __________________________________________________________________________    Compound                                                                      __________________________________________________________________________    1,1-Diethyl-n-propylamine hydrochloride                                                                  210° C                                      (Yield : 40%)              (sublimation)                                      Rf = 0.49                                                                     1,1-Di-n-propyl-n-butylamine hydrochloride                                                               220° C                                                                 (sublimation)                                      1,1-Diethyl-n-butylamine hydrochloride                                                                   M.P. >300° C                                (Yield : 60%)                                                                 Rf = 0.59                                                                     1-Ethyl-1-n-propyl-n-butylamine hydrochloride                                                            180° C                                      (Yield : 25%)              (sublimation)                                      Rf = 0.64                                                                     1-Ethyl-1-isobutyl-n-butylamine hydrochloride                                                            230° C                                      (Yield : 30%)              (sublimation)                                      Rf = 0.60                                                                     1,1-Dimethyl-n-octylamine hydrochloride                                                                  M.P. 111.8° C                               (Yield : 45%)                                                                 Rf = 0.65                                                                     1,3-Dimethyl-1-ethyl-n-hexylamine hydrochloride                                                          M.P. 133.3° C                               Rf = 0.56                                                                     1-Methyl-1-n-propyl-n-hexylamine hydrochloride                                                           M.P. 174.7° C                               (Yield : 60%)                                                                 Rf = 0.60                                                                     1-n-Propyl-1-isopropyl-n-butylamine hydrochloride                                                        M.P. 260° C                                                            (Decomposition)                                    1-Ethyl-1-n-propyl-n-pentylamine hydrochloride                                                           M.P. 230° C                                 (Yield : 30%)              (Decomposition)                                    Rf = 0.60                                                                     __________________________________________________________________________

EXAMPLE 4 Preparation of 1,1-dimethyl-3-ethyl-n-hexylamine acid fumarate

a. 1,1-Dimethyl-3-ethyl-n-hexylamine 1,1-Dimethyl-3-ethyl-n-hexylaminein free base form was first prepared by reacting a 30% aqueous solutionof sodium hydroxide with 1,1-dimethyl-3-ethyl-n-hexylamine hydrochoride.The free base so obtained was then extracted with ether.

1,1-Dimethyl-3-ethyl-n-hexylamine acid fumarate

To a solution of 1.74 g (0.015 mol) of fumaric acid in 300 ml of acetonewere slowly added 2.3 g (0.015 mol) of1,1-dimethyl-3-ethyl-n-hexylamine, prepared as previously described in40 ml of acetone. The mixture was stirred for 3 hours and the fumaratewhich crystallized was filtered off, washed with acetone and dried.

In this manner, 2 g of 1,1-dimethyl-3-ethyl-n-hexylamine acid fumaratewere obtained in the form of colourless crystals.

M.P. 160.6° C

Yield : 50%

In a thin layer chromatographic assay performed on silicagel plates(Merck HF 254) using a system of solvents comprising 79 parts ofbenzene, 14 parts of methanol and 7 parts of acetic acid and with iodineas revealing agent, a Rf of 0.56 was recorded.

By following the same procedure as that described above but using theappropriate starting-products, the compounds listed hereunder wereprepared.

The Rf value given for each of these compounds was determined in a thinlayer chromatographic assay using the same support, the same system ofsolvents and the same revealing agent as those mentioned in the Examplehereabove described:

    __________________________________________________________________________    Compound                                                                      __________________________________________________________________________    1,1,3-Trimethyl-n-heptylamine acid fumarate                                                               M.P. 140° C                                Rf = 0.54                                                                     1-n-Propyl-1-tert-butyl-n-butylamine acid fumarate                                                        180° C                                                                 (sublimation)                                     1,3-Dimethyl-1-n-propyl-n-pentylamine acid fumarate                                                       M.P. 114.4° C                              Rf = 0.56                                                                     1,1-Diisobutyl-n-butylamine acid fumarate                                                                 M.P. 179° C                                Rf = 0.66                                                                     __________________________________________________________________________

EXAMPLE 5 Preparation of 1-methyl-1-isobutyl-n-pentylamine neutralfumarate

a. 1-Methyl-1-isobutyl-n-pentylamine

1-Methyl-1-isobutyl-n-pentylamine in free base form was first preparedby reacting a 30% aqueous solution of sodium hydroxide with1-methyl-1-isobutyl-n-pentylamine hydrochloride.

The free base so obtained was then extracted with ether.

b. 1-Methyl-1-isobutyl-n-pentylamine neutral fumarate

While stirring, the amine in free base form so obtained was slowly addedto a solution of 2.32 g (0.02 mol) of fumaric acid in 300 ml of acetone.The fumarate slowly crystallized. Stirring was maintained for a furtherhour and the crystals which formed were filtered off, washed withacetone and dried.

In this manner, 3.1 of 1-methyl-1-isobutyl-n-pentylamine neutralfurmarate were obtained in the form of colourless crystals.

M.P. 198.4° C

Yield: 70%

Rf = 0.58 (in a thin layer chromatographic assay using the same solventsand revealing agent in Examples 2 and 3 above).

Example 6 Preparation of 1-ethyl-1-n-propyl-n-pentylamine hydrochloride

a. 2-Ethyl-2-n-propyl-hexanoic acid

Into a three-necked flask fitted with a mechanical stirrer, athermometer and two dropping-funnels, were placed 204 g of 96% sulphuricacid cooled to 5° C and 4 ml of formic acid. While maintaining themixture at a temperature of about 10° C, 23 g (0.5 mol) of formic acidand 15.8 g (0.1 mol) of 1-ethyl-1-n-propyl-n-pentanol in 100 ml ofpentane were simultaneously added. The operation of addition lasted 40minutes after which the reaction mixture was allowed to return toroom-temperature in 2 hours. The mixture was poured onto 100 g ofcrushed ice and the acid was extracted with ether. The acid was purifiedby preparing its sodium salt with an 20% aqueous solution of sodiumhydroxide. The aqueous phase was acidified with 50% hydrochloric acidand extracted with ether.

The organic fraction was then dried over magnesium sulphate andconcentrated under vacuum.

In this manner, 2-ethyl-2-n-propyl-hexanoic acid was obtained in theform of a colourless liquid.

B.P. 130-132° C under 20 mmHg

Yield : about 20%

Using the same method as that described above, the following compoundwas prepared:

    ______________________________________                                        Compound               B.P.                                                   ______________________________________                                        2-Ethyl-2-n-propyl-pentanoic acid                                                                    122° C                                                                 (12 mmHg)                                              ______________________________________                                    

b. 1-Ethyl-1-n-propyl-n-pentylamine

Into a three-necked flask equipped with a mechanical stirrer and acondenser, were introduced 70 ml of chloroform, 18 ml of concentratedsulphuric acid (d= 1.83) and 11 g (0.06 mol) of2-ethyl-2-n-propylhexanoic acid prepared as described above. The mixturewas heated to 50° C and while stirring 7.5 g of sodium azide in powderform were added. The operation of addition lasted 90 minutes after whichthe reaction mixture was heated to 50° C for 2 hours. The mixture wasthen neutralized with a 40% aqueous solution of sodium hydroxidepreviously cooled to 0° C. The amine was extracted with ether and theethereal phase was washed with water and dried over magnesium sulphate.The ether was evaporated out under vacuum and the oil so obtained wastaken up in dry ether, which provided 1-ethyl-1-n-propyl-n-pentylaminein free base form.

Using the same method as that described above, the following compoundwas prepared:

    ______________________________________                                        Compound               B.P.                                                   ______________________________________                                        1,1-Di-n-propyl-n-butylamine                                                                         190.5-195° C                                                           (742 mm Hg)                                            ______________________________________                                    

c. 1-Ethyl-1-n-propyl-n-pentylamine hydrochloride

The hydrochloride of the amine, previously obtained, was precipitated bybubbling dry gaseous hydrochloric acid through the solution of the saidamine.

In this manner, 1-ethyl-1-n-propyl-n-pentylamine hydrochloride wasobtained in the form of colourless crystals which sublimated from 200° C

Yield: 45%

By following the same procedure as that described above, the followingcompounds were prepared:

    __________________________________________________________________________    Compound                                                                      __________________________________________________________________________    1,1-Di-n-propyl-n-butylamine hydrochloride                                                               220° C                                                                 (sublimation)                                      1-Ethyl-1-n-propyl-n-butylamine hydrochloride                                                            180° C                                                                 (sublimation)                                      1-Ethyl-1-isobutyl-n-butylamine hydrochloride                                                            230° C                                                                 (sublimation)                                      1-n-Propyl-1-isobutyl-n-butylamine hydrochloride                                                         M.P. 260° C                                 1-n-Propyl-1-isopropyl-n-butylamine hydrochloride                                                        M.P. 260° C                                                            (decomposition)                                    1,1-Di-n-propyl-3-butyn-1-ylamine hydrochloride                                                          262° C                                                                 (sublimation and decomposition)                    __________________________________________________________________________

EXAMPLE 7 Preparation of 1,1-di-(2-propen-1-yl)-3-buten-1-ylamineoxalate

a. 1,1-Di-(2-propen-1-yl)-3-buten-1-ylamine (or triallylmethylamine)

Under nitrogen atmosphere, 13.4 g (0.2 mol) of allyl cyanide in 20 ml ofdry ether were added to a solution of 0.4 mol of allyl magnesium bromidein 350 ml of ether. The operation of addition lasted one hour while theether was lightly refluxed. After this, the reaction medium was heatedto boiling for 4 hours. After cooling, the mixture was poured into 200ml of a saturated solution of ammonium chloride. The ethereal phase wasseparated out, washed with water, dried over magnesium sulphate andevaporated under vacuum. The oil so obtained was distilled under reducedpressure.

In this manner, 14 g of 1,1-di-(2-propen-1yl)-3-buten-1-ylamine wereobtained in the form of a slightly yellow liquid.

B.P. 79°-80° C (under 15 mmHg)

Yield: 46%

By following the same procedure as that described above the followingcompound was prepared:

    ______________________________________                                        Compound                                                                      ______________________________________                                        1,1-Di-n-propyl-n-butylamine                                                                         n.sub.D.sup.21 = 1.4349                                ______________________________________                                    

b. 1,1-Di-(2-propen-1-yl)-3-buten-1-ylamine oxalate

While stirring, 3 g (about 0.02 mol) or1,1-di-(2-propen-1-yl)-3-buten-1-ylamine, prepared as described above,in 20 ml of ether were added to 2.5 g (about 0.02 mol) of hydratedoxalic acid (2 molecules of hydration water) in 300 ml of ether.

Stirring was maintained for 30 minutes and then the colourless crystalswhich precipitated were filtered out. The crystals were washed withether and recrystallized from ethyl acetate.

In this manner, 4 g of 1,1-di-(2-propen-1-yl)-3-buten-1-ylamine oxalatewere obtained.

M.P. 96.2° C

Yield: 70%

By following the same procedure as that described above but usinghydrochloric acid in place of oxalic acid, the following compound wasprepared:

    ______________________________________                                        Compound                                                                      ______________________________________                                        1,1-Di-n-propyl-n-butylamine hydrochloride                                                             220° C                                                                 (sublimation)                                        ______________________________________                                    

EXAMPLE 8 Preparation of 1,1-di-n-propyl-2-propyn-1-ylaminehydrochloride

a. 1,1-Di-n-propyl-2-propyn-1-ol

A 2-liter three-necked flask fitted with a mechanical stirrer, acondenser, a dip tube and a dropping-funnel was placed in a fumecupboard. Into the flask previously cooled in a bath of carbon-dioxidesnow in acetone, was introduced 1 liter of liquid ammonia. Acetylene,previously purified by passing through a trap containing carbon-dioxidesnow, bubbling in a sulphuric acid solution and drying over causticpotash, was then bubbled through the reaction medium.

To the acetylene solution in ammonia were added 23 g of finely dividedsodium. The bubbling of acetylene was maintained for 1 hour after theintroduction of the sodium. After that, 114 g (1 mol) of di-n-propylketone were added and the acetylene flow was maintained for 1 hour afterwhich 500 ml of ether were added and the mixture was allowed to standfor 12 hours at room-temperature. It was then hydrolysed by adding dampether followed by crushed ice. After acidification with 10% sulphuricacid, the ethereal phase was separated out, dried over magnesiumsulphate and concentrated under reduced pressure.

In this manner, 45 g of 1,1-di-n-propyl-2-propyn-1-ol were collectedafter distillation, which represents a yield of 32%.

B.P. 68°-70° C

b. 1,1-Di-n-propyl-1-chloro-2-propyne

Into a 3-necked flask fitted with a magnetic stirrer, a thermometer anda dropping-funnel, were placed 6.5 g of freshly prepared cuprouschloride, 9.1 g of calcium chloride, 0.020 g of copper-bronze powder and71 ml of concentrated and iced hydrochloric acid (d = 1.19). Whilestirring, 23 g of 1,1-di-n-propyl-2-propyn-1-ol, prepared as describedabove were added to the mixture maintained at 10° C.

The operation of adding the alcohol lasted 30 minutes and then thereaction mixture was allowed to stand for 2 hours at room-temperature.The supernating part of the mixture was decanted into a dropping-funneland washed with twice 15 ml of concentrated and iced hydrochloric acidand then with three times 20 ml of distilled water. After drying overpotassium carbonate, the mixture was distilled to give the desiredproduct.

In this manner, 17 g of 1,1-di-n-propyl-1-chloro-2-propyne in the formof a limpid and colourless liquid were obtained which represents a yieldof 65%.

B.P. 63°-65° C under 14 mm Hg.

c. 1,1-Di-n-propyl-2-propyn-1-ylamine

To a suspension of sodium amide in liquid ammonia, prepared from 6.9 gof sodium and 250 ml of liquid ammonia, were added 17 g of1,1-di-n-propyl-1-chloro-2-propyne in 50 ml of anhydrous ethyl ether.The operation of adding the chlorinated derivative lasted one hour.Stirring of the mixture was maintained for 2 hours and then 300 ml ofanhydrous ethyl ether were added.

The reaction medium was allowed to stand for 12 hours after which theammonia was evaporated off and 100 g of crushed ice were added. Theethereal phase was separated out and the basic phase was extracted with300 ml of a 10% aqueous solution of hydrochloric acid. The amine wasrecovered by adding concentrated and iced caustic soda and againextracting with ether.

In this manner, 1,1-di-n-propyl-2-propyn-1-ylamine was obtained in theform of its free base.

By following the same method as that described above, the compoundslisted below were prepared:

    ______________________________________                                        Compound                                                                      ______________________________________                                        1,1-Dimethyl-2-propyn-1-ylamine                                                                     M.P. 18° C                                       1,1-Diethyl-2-propyn-1-ylamine                                                                      B.P. 71-72° C                                                          (90 mm Hg)                                              ______________________________________                                    

d. 1,1-Di-n-propyl-2-propyn-1-ylamine hydrochloride

The ethereal solution of amine previously obtained was dried overmagnesium sulphate and the hydrochloride of this amine was thenprecipitated by bubbling dry gaseous hydrochloric acid. The crystals soobtained were separated out and dried in a dessicator in the presence ofcaustic potash.

In this manner, 12 g of 1,1-di-n-propyl-2-propyn-1-ylamine hydrochloridewere obtained in the form of colourless crystals, which represents ayield of 68%.

M.P. 200° C (with decomposition).

EXAMPLE 9 Preparation of 1,1-diethyl-2-pentyn-1-ylamine hydrochloride

a. 1,1-Diethyl-2-pentyn-1-ylamine

Into a 3 necked-flask fitted with a mechanical stirrer, a verticalcondenser and a dropping-funnel, was prepared a suspension of sodiumamide from 150 ml of liquid ammonia, 2.4 g of sodium and some crystalsof ferric nitrate. To this suspension, was added, in 30 minutes, asolution of 11 g of 1,1-diethyl-2-propyn-1-ylamine, prepared aspreviously described, and 20 ml of anhydrous ethyl ester. When theoperation of addition was finished, the stirring of the mixture wasmaintained for 30 minutes and a solution of 15 g of dry ethyl bromide in30 ml of anhydrous ethyl ether was introduced drop-by-drop into thereaction mixture. The operation of adding the ethyl bromide lasted onehour, after which stirring of the mixture was maintained for 4 hours.The reaction medium was then allowed to stand for 12 hours so that theammonia could evaporate and 50 g of crushed ice were added. The etherealphase was separated out, dried over magnesium sulphate and thenevaporated out under reduced pressure.

In this manner, 8 g of 1,1-diethyl-2-pentyn-1-ylamine were obtained,after distillation, in the form of a colourless liquid.

B.P. 62°-63° C under 15 mm Hg.

Yield: 57%

By following the same procedure as that described above but using theappropriate starting-products, the following compound was prepared:

    ______________________________________                                        Compound               B.P.                                                   ______________________________________                                        1,1-Di-n-propyl-2-pentyn-1-ylamine                                                                   92-94° C                                        (Yield : 55%)          (15 mm Hg)                                             ______________________________________                                    

b. 1,1-Diethyl-2-pentyn-1-ylamine hydrochloride

The hydrochloride of the amine previously obtained was prepared bytreating an anhydrous ethereal solution of this amine with dry gaseoushydrochloric acid. By evaporating the ether and drying the crystals soobtained in a dessicator and in the presence of caustic potash,1,1-diethyl-2-pentyn-1-ylamine hydrochloride was obtained in the form ofa white powder.

M.P. 85° C

Yield: 100%

By following the same procedure as that described above, the followingcompound was prepared:

    ______________________________________                                        Compound               M.P.                                                   ______________________________________                                        1,1-Di-n-propyl-2-pentyn-1-ylamine                                            hydrochloride          118° C                                          (Yield : 100%).                                                               ______________________________________                                    

EXAMPLE 10 Preparation of 1,1-diethyl-2-penten-1-ylamine hydrochloride

In 40 ml of heptane, 3.5 g of 1,1-diethyl-2-pentyn-1-ylamine werehydrogenated in the presence of 50 mg of a Lindlar catalyst (catalystformed from palladium, sodium carbonate and lead oxide). The addition ofhydrogen on the triple bond was facilitated by maintaining the mixtureunder stirring and heating it to a temperature of about 50° C. Theabsorption of 560 cm³ of hydrogen was achieved in 90 minutes. Afterevaporating the solvent, the desired hydrochloride was isolated byadding dry gaseous hydrochloric acid. The crystals so obtained weredried in a dessicator in the presence of caustic potash.

In this manner, 1,1-diethyl-2-penten-1-ylamine hydrochloride wasobtained in the form of a white powder.

M.P. 200° C with sublimation.

Yield: 100%

By following the same procedure as that described above, the followingcompound was prepared:

    ______________________________________                                        Compound                                                                      ______________________________________                                        1,1-Di-n-propyl-2-penten-1-ylamine hydrochloride                                                        200° C                                       (Yield : 100%)            (sublimation)                                       ______________________________________                                    

EXAMPLE 11

A hard-gelatin capsule containing the following ingredients was preparedin accordance with known pharmaceutical techniques:

    ______________________________________                                               Ingredients      mg                                                    ______________________________________                                        1,1-Di-n-propyl-n-butylamine                                                  hydrochloride            5                                                    Milk sugar              45                                                                            50                                                    ______________________________________                                    

We claim:
 1. Method of treating Parkinson's disease and correctingextra-pyramidal disturbances provoked by neuroleptics comprising theadministration to a subject in need of such treatment of an effectivedose of at least one methylamine derivative of the formula: ##STR12## ora pharmaceutically acceptable acid addition salt thereof, in which R₁represents ethyl, R₃ represents methyl or ethyl, and R₂ representsa.ethyl, n-propyl, isopropyl, isobutyl, tert-butyl, or 1-butenyl when R₃is ethyl, or b. n-butyl or isobutyl when R₃ is methyl.
 2. Method fortreating Parkinson's disease and correcting the extra-pyramidaldisturbances provoked by the neuroleptics comprising the administrationto a subject in need of such treatment of an effective dose of1,1-di-n-propyl-n-butylamine or a pharmaceutically acceptable acidaddition salt thereof.
 3. Method according to claim 2 whereby thepharmaceutically acceptable acid addition salt is the hydrochloride orthe acid fumarate.
 4. A pharmaceutical or veterinary composition for usein the treatment of Parkinson's disease and for the correction ofextra-pyramidal disturbances provoked by neuroleptics comprising as anessential active ingredient at least one methylamine derivative of theformula: ##STR13## in which R₁ represents ethyl, R₃ represents methyl orethyl, and R₂ representsa. ethyl, n-propyl, isopropyl, isobutyl,tert-butyl, or 1-butenyl when R₃ is ethyl, or b. n-butyl or isobutylwhen R₃ is methyl,or a pharmaceutically acceptable acid addition salt ofthe said derivative, in association with a pharmaceutical carrier orexcipient therefor.
 5. A pharmaceutical or veterinary composition foruse in the treatment of Parkinson's disease and for the correction ofextra-pyramidal disturbances provoked by neuroleptics comprising as anessential active ingredient 1,1-di-n-propyl-n-butylamine or apharmaceutically acceptable acid addition salt thereof, in associationwith a pharmaceutical carrier or excipient therefor.
 6. A pharmaceuticalor veterinary composition according to claim 5 whereby thepharmaceutically acceptable acid addition salt is the hydrochloride orthe acid fumarate.